This program project will investigate the role of hyperglycemia and insulin resistance in the excess cardiovascular disease due to diabetes. The program will utilize innovative and multi-disciplinary approaches to address the overall unifying theme that elevate glucose and/of insulin resistance leads to accelerated cardiovascular disease by increasing oxidative stress and inflammatory signals in the vessel wall. A hypothesis developed in the initial funding period will be expanded to evaluate the role of lipoxygenase (LO) activation in mediating the oxidative and inflammatory changes associated with atherosclerosis and vascular injury. A strength of the program will be the use of both small and large animal models to more clearly evaluate the genetic and molecular mechanisms leading to cardiovascular disease in diabetes. These models will also allow the evaluation of potentially therapeutic to prevent the accelerated atherosclerosis and injury response in people with diabetes. The program involves 4 projects and 3 cores. Project 1 will examine the hypothesis that activation of LO pathway can play a role in atherosclerosis and vascular injury by inducing the transcriptional regulation of key genes which regulate vascular smooth muscle cell migration and matrix remodeling. A unique aspect of this project will be the use of novel ribozymes and animal models to test the in vivo role of oxidative stress and 12-LO in these processes. Project 2 will test the hypothesis that glucose and the diabetic state induce LO expression in aortic endothelial cells and that arachidonic or linoleic acid derived oxidative lipids activate key signalling mechanisms and oxidative phospholipids which lead to the binding of monocytes to the vessel wall. This project will utilize novel ribozymes, mouse, and swine models in the cores. Project 3 will mechanistically evaluate the role of helix-loop-helix transcription factors such as Id3 in accelerated VSMC growth response to injury in insulin resistant and diabetic states. Studies will utilizes chemokines, and chemokine receptors determine monocyte recruitment to atherosclerotic lesions and b) the increased rate of atherosclerosis in diabetes can in part be explained by a more robust or earlier expression of these molecules. A novel aspect of this project will be the use of in isolated perfused carotid artery model and the therapeutic and mechanistic actions of a novel anti- inflammatory agent Lisofylline in appropriate mouse models. The synergy between the projects and use of the cores will greatly accelerate the pace of this research to understand the mechanisms of accelerated macrovascular disease in diabetes. The results form this program should provide new therapeutic advances to reduce the rate of cardiovascular disease in diabetes.